Hans Matter

Publications of Hans Matter

• Development of in silico filters to predict activation of the pregnane X receptor (PXR) by structurally diverse drug-like molecules.

  Authors: Hans Matter, Lennart T Anger, Clemens Giegerich, Stefan Güssregen, Gerhard Hessler, Karl-Heinz Baringhaus

  Bioorganic & medicinal chemistry. 04/2012;

  The pregnane X receptor (PXR), a member of the nuclear hormone superfamily, regulates the expression of several enzymes and transporters involved in metabolically relevant processes. The significantThe pregnane X receptor (PXR), a member of the nuclear hormone superfamily, regulates the expression of several enzymes and transporters involved in metabolically relevant processes. The significant induction of CYP450 enzymes by PXR, in particular CYP3A4, might significantly alter the metabolism of prescribed drugs. In order to early identify molecules in drug discovery with a potential to activate PXR as antitarget, we developed fast and reliable in silico filters by ligand-based QSAR techniques. Two classification models were established on a diverse dataset of 434 drug-like molecules. A second augmented set allowed focusing on interesting regions in chemical space. These classifiers are based on decision trees combined with a genetic algorithm based variable selection to arrive at predictive models. The classifier for the first dataset on 29 descriptors showed good performance on a test set with a correct classification of both 100% for PXR activators and non-activators plus 87% for activators and 83% for non-activators in an external dataset. The second classifier then correctly predicts 97% activators and 91% non-activators in a test set and 94% for activators and 64% non-activators in an external set of 50 molecules, which still qualifies for application as a filter focusing on PXR activators. Finally a quantitative model for PXR activation for a subset of these molecules was derived using a regression-tree approach combined with GA variable selection. This final model shows a predictive r(2) of 0.774 for the test set and 0.452 for an external set of 33 molecules. Thus, the combination of these filters consistently provide guidelines for lowering PXR activation in novel candidate molecules.

• Fragment Deconstruction of Small, Potent Factor Xa Inhibitors: Exploring the Superadditivity Energetics of Fragment Linking in Protein-Ligand Complexes.

  Authors: Marc Nazaré, Hans Matter, David W Will, Michael Wagner, Matthias Urmann, Jörg Czech, Herman Schreuder, Armin Bauer, Kurt Ritter, Volkmar Wehner

  Angewandte Chemie (International ed. in English). 12/2011;

  The superadditivity of fragment linking on affinities was quantified by systematic deconstruction of a fXa inhibitor. In their Communication (DOI: 10.1002/anie.201107091), M. Nazaré, H. Matter, andThe superadditivity of fragment linking on affinities was quantified by systematic deconstruction of a fXa inhibitor. In their Communication (DOI: 10.1002/anie.201107091), M. Nazaré, H. Matter, and co-workers show that by connecting two fragments with a single bond, a linker contribution of -14.0 kJ mol(-1) results, which corresponds to an affinity improvement of about 2.5 orders of magnitude relative to the sum of fragment affinities.

• Fragment deconstruction of small, potent factor Xa inhibitors: exploring the superadditivity energetics of fragment linking in protein-ligand complexes.

  Authors: Marc Nazaré, Hans Matter, David W Will, Michael Wagner, Matthias Urmann, Jörg Czech, Herman Schreuder, Armin Bauer, Kurt Ritter, Volkmar Wehner

  Angewandte Chemie (International ed. in English). 12/2011; 51(4):905-11.

  More than just the sum of its parts: The superadditivity effect of fragment linking on ΔG was quantified by deconstructing two fXa inhibitors with congeneric fragments, but different linkers. ByMore than just the sum of its parts: The superadditivity effect of fragment linking on ΔG was quantified by deconstructing two fXa inhibitors with congeneric fragments, but different linkers. By connecting both fragments with a single bond, a high linker contribution ΔG(link) of -14.0 kJ mol(-1) results, which corresponds to an improvement in affinity by around 2.5 orders of magnitude relative to the sum of fragment ΔG values.

• Structure-based optimization of potent 4- and 6-azaindole-3-carboxamides as renin inhibitors.

  Authors: Bodo Scheiper, Hans Matter, Henning Steinhagen, Zsolt Böcskei, Valérie Fleury, Gary McCort

  Bioorganic & medicinal chemistry letters. 09/2011; 21(18):5480-6.

  The control of hypertension and associated cardiovascular risk factors is possible by selective inhibition of the aspartyl protease renin due to its unique position in the renin-angiotensin system.The control of hypertension and associated cardiovascular risk factors is possible by selective inhibition of the aspartyl protease renin due to its unique position in the renin-angiotensin system. Starting from a previously disclosed series of potent and nonchiral indole-3-carboxamides, we further explored this motif by structure-based drug design guided by X-ray crystallography in combination with efficient parallel synthesis. This resulted in the discovery of 4- or 6-azaindole derivatives with remarkable potency for renin inhibition. The best compound from these series showed an IC(50) value of 1.3 nM.

• Structure-based design and optimization of potent renin inhibitors on 5- or 7-azaindole-scaffolds.

  Authors: Hans Matter, Bodo Scheiper, Henning Steinhagen, Zsolt Böcskei, Valérie Fleury, Gary McCort

  Bioorganic & medicinal chemistry letters. 09/2011; 21(18):5487-92.

  The selective inhibition of the aspartyl protease renin is of high interest to control hypertension and associated cardiovascular risk factors. Following on preceding contributions, we report hereinThe selective inhibition of the aspartyl protease renin is of high interest to control hypertension and associated cardiovascular risk factors. Following on preceding contributions, we report herein on the optimization of two series of azaindoles to arrive at potent and non-chiral renin inhibitors. The previously discovered azaindole scaffold was further explored by structure-based drug design in combination with parallel synthesis. This results in the identification of novel 5- or 7-azaindole derivatives with remarkable potency for renin inhibition. The best compounds on both series show IC(50) values between 3 and 8nM.

• Sulfonylthiadiazoles with an unusual binding mode as partial dual peroxisome proliferator-activated receptor (PPAR) γ/δ agonists with high potency and in vivo efficacy.

  Authors: Stefanie Keil, Hans Matter, Karl Schönafinger, Maike Glien, Magali Mathieu, Jean-Pierre Marquette, Nadine Michot, Silke Haag-Diergarten, Matthias Urmann, Wolfgang Wendler

  ChemMedChem. 03/2011; 6(4):633-53.

  Compounds that simultaneously activate the peroxisome proliferator-activated receptor (PPAR) subtypes PPARγ and PPARδ have the potential to effectively target dyslipidemia and type II diabetes in aCompounds that simultaneously activate the peroxisome proliferator-activated receptor (PPAR) subtypes PPARγ and PPARδ have the potential to effectively target dyslipidemia and type II diabetes in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ agonists, such as edema and weight gain, are expected to be overcome by using partial instead of full agonists for this nuclear receptor family. Herein we report the discovery, synthesis, and optimization of a novel series of sulfonylthiadiazoles that are active as partial agonists. The initial compound 6 was discovered by high-throughput screening as a moderate partial PPARδ agonist; its optimization was based on the X-ray crystal structure in complex with PPARδ. In contrast to other PPARδ agonists, this ligand does not interact directly with residues from the activation helix AF-2, which might be linked to its partial agonistic effect. Interestingly, the thiadiazole moiety fills a novel subpocket, which becomes accessible after moderate conformational rearrangement. The optimization was focused on introducing conformational constraints and replacing intramolecular hydrogen bonding interactions. Highly potent molecules with activity as dual partial PPARγ/δ agonists in the low nanomolar range were then identified. One of the most active members, compound 20 a, displayed EC₅₀ values of 1.6 and 336 nM for PPARδ and γ, respectively. The X-ray crystal structure of its complex with PPARδ confirms our design hypothesis. Compound 20 a clearly displayed in vivo activity in two chronic mice studies. Lipids were modified in a beneficial way in normolipidemic mice, and the development of overt diabetes could be prevented in pre-diabetic db/db mice. However, body weight gain was similar to that observed with the PPARγ agonist rosiglitazone. Hence, active compounds from this series can be considered as valuable tools to elucidate the complex roles of dual PPARγ/δ agonists for potential treatment of metabolic syndrome.

• Discovery and optimization of a new class of potent and non-chiral indole-3-carboxamide-based renin inhibitors.

  Authors: Bodo Scheiper, Hans Matter, Henning Steinhagen, Ulrich Stilz, Zsolt Böcskei, Valérie Fleury, Gary McCort

  Bioorganic & medicinal chemistry letters. 11/2010; 20(21):6268-72.

  Selective inhibition of the aspartyl protease renin has gained attraction as an interesting approach to control hypertension and associated cardiovascular risk factors given its unique position inSelective inhibition of the aspartyl protease renin has gained attraction as an interesting approach to control hypertension and associated cardiovascular risk factors given its unique position in the renin-angiotensin system. Using a combination of high-throughput screening, parallel synthesis, X-ray crystallography and structure-based design, we identified and optimized a novel series of potent and non-chiral indole-3-carboxamides with remarkable potency for renin. The most potent compound 5k displays an IC(50) value of 2nM.

• Evidence for C-Cl/C-Br...pi interactions as an important contribution to protein-ligand binding affinity.

  Authors: Hans Matter, Marc Nazaré, Stefan Güssregen, David W Will, Herman Schreuder, Armin Bauer, Matthias Urmann, Kurt Ritter, Michael Wagner, Volkmar Wehner

  Angewandte Chemie (International ed. in English). 02/2009; 48(16):2911-6.

  Attractive chlorine: Noncovalent interactions between chlorine or bromine atoms and aromatic rings in proteins open up a new method for the manipulation of molecular recognition. Substitution atAttractive chlorine: Noncovalent interactions between chlorine or bromine atoms and aromatic rings in proteins open up a new method for the manipulation of molecular recognition. Substitution at distinct positions of two factor Xa inhibitors improves the free energy of binding by interaction with a tyrosine unit. The generality of this motif was underscored by multiple crystal structures as well as high-level quantum chemical calculations (see picture).

• Matrix metalloproteinase target family landscape: a chemometrical approach to ligand selectivity based on protein binding site analysis.

  Authors: Bernard Pirard, Hans Matter

  Journal of medicinal chemistry. 01/2006; 49(1):51-69.

  To gain insight into the structural determinants for the matrix metalloproteinase (MMP) family, we characterized the binding sites of 56 MMP structures and one TACE (tumor necrosis factor alphaTo gain insight into the structural determinants for the matrix metalloproteinase (MMP) family, we characterized the binding sites of 56 MMP structures and one TACE (tumor necrosis factor alpha converting enzyme) structure using molecular interaction fields (MIFs). These MIFs were produced by two approaches: the GRID force field and the knowledge-based potential DrugScore. The subsequent statistical analysis using consensus principal component analysis (CPCA) for the entire binding site and each subpockets revealed both approaches to encode similar information about discriminating regions. However, the relative importance of the probes varied between both approaches. The CPCA models provided the following ranking of the six subpockets based on the opportunity for selective interactions with different MMPs: S1' > S2, S3, S3' > S1, S2'. The interpretation of these models agreed with experimental binding modes inferred from crystal structures or docking.

• Multiple-ligand-based virtual screening: methods and applications of the MTree approach.

  Authors: Gerhard Hessler, Marc Zimmermann, Hans Matter, Andreas Evers, Thorsten Naumann, Thomas Lengauer, Matthias Rarey

  Journal of medicinal chemistry. 11/2005; 48(21):6575-84.

  We present a novel approach for ligand-based virtual screening by combining query molecules into a multiple feature tree model called MTree. All molecules are described by the established featureWe present a novel approach for ligand-based virtual screening by combining query molecules into a multiple feature tree model called MTree. All molecules are described by the established feature tree descriptor, which is derived from a topological molecular graph. A new pairwise alignment algorithm leads to a consistent topological molecular alignment based on chemically reasonable matching of corresponding functional groups. These multiple feature tree models find application in ligand-based virtual screening to identify new lead structures for chemical optimization. Retrospective virtual screening with MTree models generated for angiotensin-converting enzyme and the alpha1a receptor on a large candidate database yielded enrichment factors up to 71 for the first 1% of the screened database. MTree models outperformed database searches using single feature trees in terms of hit rates and quality and additionally identified alternative molecular scaffolds not included in any of the query molecules. Furthermore, relevant molecular features, which are known to be important for affinity to the target, are identified by this new methodology.

• Virtual screening of biogenic amine-binding G-protein coupled receptors: comparative evaluation of protein- and ligand-based virtual screening protocols.

  Authors: Andreas Evers, Gerhard Hessler, Hans Matter, Thomas Klabunde

  Journal of medicinal chemistry. 09/2005; 48(17):5448-65.

  In this paper, we compare protein- and ligand-based virtual screening techniques for identifying the ligands of four biogenic amine-binding G-protein coupled receptors (GPCRs). For the screening ofIn this paper, we compare protein- and ligand-based virtual screening techniques for identifying the ligands of four biogenic amine-binding G-protein coupled receptors (GPCRs). For the screening of the virtual compound libraries, we used (1) molecular docking into GPCR homology models, (2) ligand-based pharmacophore and Feature Tree models, (3) three-dimensional (3D)-similarity searches, and (4) statistical methods [partial least squares (PLS) and partial least squares discriminant analysis (PLS-DA) models] based on two-dimensional (2D) molecular descriptors. The comparison of the different methods in retrieving known antagonists from virtual libraries shows that in our study the ligand-based pharmacophore-, Feature Tree-, and 2D quantitative structure-activity relationship (QSAR)-based screening techniques provide enrichment factors that are higher than those provided by molecular docking into the GPCR homology models. Nevertheless, the hit rates achieved when docking with GOLD and ranking the ligands with GoldScore (up to 60% among the top-ranked 1% of the screened databases) are still satisfying. These results suggest that docking into GPCR homology models can be a useful approach for lead finding by virtual screening when either little or no information about the active ligands is available.

• Structural analysis of isoform-specific inhibitors targeting the tetrahydrobiopterin binding site of human nitric oxide synthases.

  Authors: Hans Matter, H S Arun Kumar, Roman Fedorov, Armin Frey, Peter Kotsonis, Elisabeth Hartmann, Lothar G Fröhlich, Andreas Reif, Wolfgang Pfleiderer, Peter Scheurer, Dipak K Ghosh, Ilme Schlichting, Harald H H W Schmidt

  Journal of medicinal chemistry. 08/2005; 48(15):4783-92.

  Nitric oxide synthesized from l-arginine by nitric oxide synthase isoforms (NOS-I-III) is physiologically important but also can be deleterious when overproduced. Selective NOS inhibitors are ofNitric oxide synthesized from l-arginine by nitric oxide synthase isoforms (NOS-I-III) is physiologically important but also can be deleterious when overproduced. Selective NOS inhibitors are of clinical interest, given their differing pathophysiological roles. Here we describe our approach to target the unique NOS (6R,1'R,2'S)-5,6,7,8-tetrahydrobiopterin (H(4)Bip) binding site. By a combination of ligand- and structure-based design, the structure-activity relationship (SAR) for a focused set of 41 pteridine analogues on four scaffolds was developed, revealing selective NOS-I inhibitors. The X-ray crystal structure of rat NOS-I dimeric-oxygenase domain with H(4)Bip and l-arginine was determined and used for human isoform homology modeling. All available NOS structural information was subjected to comparative analysis of favorable protein-ligand interactions using the GRID/concensus principal component analysis (CPCA) approach to identify the isoform-specific interaction site. Our interpretation, based on protein structures, is in good agreement with the ligand SAR and thus permits the rational design of next-generation inhibitors targeting the H(4)Bip binding site with enhanced isoform selectivity for therapeutics in pathology with NO overproduction.

• Probing the subpockets of factor Xa reveals two binding modes for inhibitors based on a 2-carboxyindole scaffold: a study combining structure-activity relationship and X-ray crystallography.

  Authors: Marc Nazaré, David W Will, Hans Matter, Herman Schreuder, Kurt Ritter, Matthias Urmann, Melanie Essrich, Armin Bauer, Michael Wagner, Jörg Czech, Martin Lorenz, Volker Laux, Volkmar Wehner

  Journal of medicinal chemistry. 08/2005; 48(14):4511-25.

  Structure-activity relationships within a series of highly potent 2-carboxyindole-based factor Xa inhibitors incorporating a neutral P1 ligand are described with particular emphasis on the structuralStructure-activity relationships within a series of highly potent 2-carboxyindole-based factor Xa inhibitors incorporating a neutral P1 ligand are described with particular emphasis on the structural requirements for addressing subpockets of the factor Xa enzyme. Interactions with the subpockets were probed by systematic substitution of the 2-carboxyindole scaffold, in combination with privileged P1 and P4 substituents. Combining the most favorable substituents at the indole nucleus led to the discovery of a remarkably potent factor Xa inhibitor displaying a K(i) value of 0.07 nM. X-ray crystallography of inhibitors bound to factor Xa revealed substituent-dependent switching of the inhibitor binding mode and provided a rationale for the SAR obtained. These results underscore the key role played by the P1 ligand not only in determining the binding affinity of the inhibitor by direct interaction but also in modifying the binding mode of the whole scaffold, resulting in a nonlinear SAR.

• Structural requirements for factor Xa inhibition by 3-oxybenzamides with neutral P1 substituents: combining X-ray crystallography, 3D-QSAR, and tailored scoring functions.

  Authors: Hans Matter, David W Will, Marc Nazaré, Herman Schreuder, Volker Laux, Volkmar Wehner

  Journal of medicinal chemistry. 06/2005; 48(9):3290-312.

  The design, synthesis, and structure-activity relationship of 3-oxybenzamides as potent inhibitors of the coagulation protease factor Xa are described on the basis of X-ray structures, privilegedThe design, synthesis, and structure-activity relationship of 3-oxybenzamides as potent inhibitors of the coagulation protease factor Xa are described on the basis of X-ray structures, privileged structure motifs, and SAR information. A total of six X-ray structures of fXa/inhibitor complexes led us to identify the major protein-ligand interactions. The binding mode is characterized by a lipophilic dichlorophenyl substituent interacting with Tyr228 in the protease S1 pocket, while polar parts are accommodated in S4. This alignment in combination with docking allowed derivation of 3D-QSAR models and tailored scoring functions to rationalize biological affinity and provide guidelines for optimization. The resulting models showed good correlation coefficients and predictions of external test sets. Furthermore, they correspond to binding site topologies in terms of steric, electrostatic, and hydrophobic complementarity. Two approaches to derive tailored scoring functions combining binding site and ligand information led to predictive models with acceptable predictions of the external set. Good correlations to experimental affinities were obtained for both AFMoC (adaptation of fields for molecular comparison) and the novel TScore function. The SAR information from 3D-QSAR and tailored scoring functions agrees with all experimental data and provides guidelines and reasonable activity estimations for novel fXa inhibitors.

• QSAR-by-NMR: quantitative insights into structural determinants for binding affinity by analysis of 1H/15N chemical shift differences in MMP-3 ligands.

  Authors: Hans Matter, Manfred Schudok, Bettina Elshorst, Doris M Jacobs, Krishna Saxena, Herbert Kogler

  Bioorganic & medicinal chemistry letters. 05/2005; 15(7):1779-83.

  A novel strategy is applied to obtain quantitative insights on factors influencing biological affinity in protein-ligand complexes. This approach is based on the detection of ligand binding by (15)NA novel strategy is applied to obtain quantitative insights on factors influencing biological affinity in protein-ligand complexes. This approach is based on the detection of ligand binding by (15)N and (1)H amide chemical shift differences in two-dimensional (15)N-heteronuclear single-quantum correlation spectra. Essential structural features linked to affinity can be extracted using statistical analysis of (15)N and (1)H amide chemical shift differences in congeneric series relative to uncomplexed protein spectra, as demonstrated for 20 MMP-3 inhibitors in complex with human matrix metalloproteinase stromelysin (MMP-3). The statistical analysis using PLS led to a significant model, while its chemical interpretation, highlighting the importance of particular residues for affinity, are in agreement to an X-ray structure of one key compound in the homologue MMP-8 binding site.

• Custom chemical microarray production and affinity fingerprinting for the S1 pocket of factor VIIa.

  Authors: Stefan Dickopf, Michael Frank, Hans-Dieter Junker, Sabine Maier, Günther Metz, Holger Ottleben, Harald Rau, Nathalie Schellhaas, Kristina Schmidt, Renate Sekul, Cecile Vanier, Dirk Vetter, Jörg Czech, Martin Lorenz, Hans Matter, Manfred Schudok, Herman Schreuder, David W Will, Hans Peter Nestler

  Analytical biochemistry. 01/2005; 335(1):50-7.

  The goal of this study was to explore the applicability of surface plasmon resonance (SPR)-based fragment screening to identify compounds that bind to factor VIIa (FVIIa). Based on pharmacophoreThe goal of this study was to explore the applicability of surface plasmon resonance (SPR)-based fragment screening to identify compounds that bind to factor VIIa (FVIIa). Based on pharmacophore models virtual screening approaches, we selected fragments anticipated to have a reasonable chance of binding to the S1-binding pocket of FVIIa and immobilized these compounds on microarrays. In affinity fingerprinting experiments, a number of compounds were identified to be specifically interacting with FVIIa and shown to fall into four structural classes. The results demonstrate that the chemical microarray technology platform using SPR detection generates unique chemobiological information that is useful for de novo discovery and lead development and allows the detection of weak interactions with ligands of low molecular weight.

• Biology and chemistry of the inhibition of nitric oxide synthases by pteridine-derivatives as therapeutic agents.

  Authors: Hans Matter, Peter Kotsonis

  Medicinal research reviews. 10/2004; 24(5):662-84.

  Inhibitors of the family of nitric oxide synthases (NOS-I-III; EC 1.14.13.39) are of interest as pharmacological agents to modulate pathologically high nitric oxide (NO) levels in inflammation,Inhibitors of the family of nitric oxide synthases (NOS-I-III; EC 1.14.13.39) are of interest as pharmacological agents to modulate pathologically high nitric oxide (NO) levels in inflammation, sepsis, and stroke. In this article, we discuss the approach for targeting the unique (6R)-5,6,7,8-tetrahydro-L-biopterin (H4Bip) binding site of NOS by appropriate inhibitors. This binding site maximally increases enzyme activity and NO production from the substrate L-arginine upon cofactor binding. The first generation of H4Bip-based NOS inhibitors was based on 4-amino H4Bip derivatives in analogy to anti-folates such as methotrexate. In addition, we discuss the structure-activity relationship of a related series of 4-oxo-pteridine derivatives. Furthermore, molecular modeling studies provide an understanding of pterin antagonism on a structural level based on favorable and unfavorable interactions between protein binding site and ligands. These techniques include 3D-QSAR (CoMFA, CoMSIA) to understand ligand affinity and GRID/consensus principal component analysis (CPCA) to learn about selectivity requirements. Collectively these approaches, in combination with the presented SAR and structural data, provide useful information for the design of novel NOS inhibitors with increased isoform selectivity.

• Novel factor Xa inhibitors based on a 2-carboxyindole scaffold: SAR of P4 substituents in combination with a neutral P1 ligand.

  Authors: Marc Nazaré, Melanie Essrich, David W Will, Hans Matter, Kurt Ritter, Matthias Urmann, Armin Bauer, Herman Schreuder, Jörg Czech, Martin Lorenz, Volker Laux, Volkmar Wehner

  Bioorganic & medicinal chemistry letters. 09/2004; 14(16):4197-201.

  A series of novel, highly potent 2-carboxyindole-based factor Xa inhibitors is described. Structural requirements for P4 ligands in combination with a neutral biaryl P1 ligand were investigated withA series of novel, highly potent 2-carboxyindole-based factor Xa inhibitors is described. Structural requirements for P4 ligands in combination with a neutral biaryl P1 ligand were investigated with the 2-carboxyindole scaffold. A diverse set of P4 substituents was identified, which, in conjunction with a biaryl P1 ligand, gave highly potent factor Xa inhibitors, which were also selective versus other proteases and efficacious in various antithrombotic secondary assays.

• Factor Xa inhibitors based on a 2-carboxyindole scaffold: SAR of neutral P1 substituents.

  Authors: Marc Nazaré, Melanie Essrich, David W Will, Hans Matter, Kurt Ritter, Matthias Urmann, Armin Bauer, Herman Schreuder, Angela Dudda, Jörg Czech, Martin Lorenz, Volker Laux, Volkmar Wehner

  Bioorganic & medicinal chemistry letters. 09/2004; 14(16):4191-5.

  A series of novel, highly potent 2-carboxyindole-based factor Xa inhibitors is described. Structural requirements for neutral ligands, which bind in the S1 pocket of factor Xa were investigated withA series of novel, highly potent 2-carboxyindole-based factor Xa inhibitors is described. Structural requirements for neutral ligands, which bind in the S1 pocket of factor Xa were investigated with the 2-carboxyindole scaffold. This privileged fragment assembly approach yielded a set of equipotent, selective inhibitors with structurally diverse neutral P1 substituents.

• Recent advances in the design of matrix metalloprotease inhibitors.

  Authors: Hans Matter, Manfred Schudok

  Current opinion in drug discovery & development. 08/2004; 7(4):513-35.

  Inhibition of matrix metalloproteases (MMPs) for the treatment of diseases, such as cancer, arthritis and other diseases associated with tissue remodeling, has become an area of intense interest inInhibition of matrix metalloproteases (MMPs) for the treatment of diseases, such as cancer, arthritis and other diseases associated with tissue remodeling, has become an area of intense interest in the pharmaceutical industry in recent years. Despite tremendous efforts over the last decade to explore individual members of this target family, along with multiple inhibitor classes, simple and effective drugs for inhibiting individual MMPs have not yet emerged. This review highlights the major developments in research into MMPs and their inhibitors, from the recent medicinal chemistry literature, with a focus on structure-based design, selectivity and pharmacokinetic (PK) properties. The increasing availability of high-resolution X-ray crystal structures for many members of this protein family makes MMPs ideally suited for structure-based design approaches, which are now routinely used in this area. The most challenging aspect of lead optimization for MMP inhibitors is in finding candidates having acceptable pharmacological, PK and selectivity profiles. Clinical trials in cancer giving disappointing results have led to discussions on how to gain adequate MMP selectivity in order to minimize side effects. Unfortunately, careful analysis of X-ray crystal structures has not suggested any simple solutions. These areas collectively constitute the main challenges in the current search for orally available MMP inhibitors, and will be discussed in this review.